Amphetamine is a flexible molecule with free rotation about the single bonds of the aminopropyl sidechain. Preliminary neuropharmacology in our laboratories has demonstrated that on at least two sites of amphetamine action in the presynaptic adrenergic neuron, the fully extended conformer of amphetamine is required. We have further demonstrated that neither the fully extended nor the folded (gauche) conformation are capable of release of norepinephrine from storage vesicles of the presynaptic adrenergic neuron. We propose to study conformationally-defined analogs of amphetamine, in which the aminopropyl sidechain is held in fixed orientations with respect to the angles of rotation about the single bonds, to find the required conformation for vesicular release and to investigate the hypothesis that by control of conformation one can control the overall effects seen with the amphetamine analog. In particular, the conformation of amphetamine and the appetite suppressant fenfluramine required for optimal anorexic effect is sought. The results are expected to afford information about the requirements for anorexic effects of amphetamine-like molecules, as well as a greater understanding of the molecular interactions and three-dimensional conformations required for the various effects of amphetamine. A control of these centrally-mediated amphetamine effects could lead to improved therapeutic agents with limited or removed abuse potential.